JP6541236B2 - インスリン様成長因子1受容体特異的抗体及びそれらの使用 - Google Patents
インスリン様成長因子1受容体特異的抗体及びそれらの使用 Download PDFInfo
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Description
GRTIDNYAの相補性決定領域(CDR)1配列(配列番号1)、
IDWGDGGX(式中、XはA又はTである)のCDR2配列(配列番号2)、及び
AMARQSRVNLDVARYDYのCDR3配列(配列番号3)
を含み、インスリン様成長因子1受容体(IGF1R)に特異的に結合する単離又は精製抗体又はその断片をさらに提供する。一実施形態において、単離又は精製抗体又はその断片は、IDWGDGGAのCDR2配列を含む。
X1VX2LX3ESGGGLVQX4GGSLRLSCAASGRTIDNYAMAWX5RQAPGKX6X7EX8VX9TIDWGDGGX10RYANSVKGRFTISRDNX11KX12TX13YLQMNX14LX15X16EDTAVYX17CAMARQSRVNLDVARYDYWGQGTX18VTVSS(配列番号4)(式中、X1はE又はQであり、X2はK又はQであり、X3はV又はEであり、X4はA又はPであり、X5はV又はSであり、X6はD又はGであり、X7はL又はRであり、X8はF又はWであり、X9はA又はSであり、X10はA又はTであり、X11はA又はSであり、X12はG又はNであり、X13はM又はLであり、X14はN又はRであり、X15はE又はRであり、X16はP又はAであり、X17はS又はYであり、X18はQ又はLである)、
又はそれと実質的に同一の配列でありうる。より具体的で非限定的な例において、単離又は精製抗体は、
本明細書においてIGF1R−5と呼ばれる、QVKLEESGGGLVQAGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVATIDWGDGGARYANSVKGRFTISRDNAKGTMYLQMNNLEPEDTAVYSCAMARQSRVNLDVARYDYWGQGTQVTVSS(配列番号5)、
本明細書においてIGF1R−5_H1と呼ばれる、EVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWVRQAPGKGLEWVSTIDWGDGGTRYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号6)、
本明細書においてIGF1R−5_H2と呼ばれる、QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWVRQAPGKGLEWVATIDWGDGGTRYANSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号7)、
本明細書においてIGF1R−5_H3と呼ばれる、QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKGLEFVATIDWGDGGTRYANSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号8)、
本明細書においてIGF1R−5_H5と呼ばれる、QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVATIDWGDGGTRYANSVKGRFTISRDNSKGTMYLQMNSLRAEDTAVYSCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号9)、及び
本明細書においてIGF1R−5_H6と呼ばれる、EVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVSTIDWGDGGTRYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号10)、
又はそれと実質的に同一の配列からなる群から選択される配列を含みうる。
a)組織試料を、検出可能な試剤に連結された本明細書に記載の1つ又は複数の単離又は精製抗体又はその断片と接触させるステップ、及び
b)組織試料において、IGF1Rに結合した抗体又はその断片に連結された検出可能な試剤を検出するステップ
を含む。
a)検出可能な試剤に連結された本明細書に記載の1つ又は複数の単離又は精製抗体又はその断片を、対象に投与するステップ、及び
b)IGF1Rに結合した抗体又はその断片に連結された検出可能な試剤を検出するステップ
を含む。
a)血液脳関門を通過する、目的の分子に連結された本明細書に記載の1つ又は複数の単離又は精製抗体又はその断片を、対象に投与するステップ
を含み、
1つ又は複数の抗体又はその断片は、BBBを通過させて目的の分子をフェリーする。前述の方法において、目的の分子は、約1kD〜約200kDaの範囲の分子量を有することがあり、目的の分子は、検出可能な試剤、治療剤、薬物、ペプチド、成長因子、サイトカイン、受容体トラップ、化合物、炭水化物部分、酵素、抗体若しくはその断片、DNAベース分子、ウイルスベクター、若しくは細胞毒性剤;検出可能な試剤、治療剤、薬物、ペプチド、酵素、抗体若しくはその断片、DNAベース分子、ウイルスベクター、若しくは細胞毒性剤が充填された1つ若しくは複数のリポソーム;又は1つ若しくは複数のナノ粒子、ナノワイヤ、ナノチューブ、若しくは量子ドットでありうる。上述の方法において、投与は、静脈内(iv)、皮下(sc)、又は筋肉内(im)でありうる。
a)対象から脳脊髄液(CSF)を回収するステップ、及び
b)標的化プロテオミクス方法を使用して、CSFにおける1つ又は複数の単離又は精製抗体又は断片に連結されたカーゴ分子の量を定量するステップ
を含む。
GRTIDNYAの相補性決定領域(CDR)1配列(配列番号1)、
IDWGDGGX(式中、XはA又はTである)のCDR2配列(配列番号2)、及び
AMARQSRVNLDVARYDYのCDR3配列(配列番号3)
を含み、インスリン様成長因子1受容体(IGF1R)に特異的に結合する単離又は精製抗体又はその断片をさらに提供する。一実施形態において、単離又は精製抗体又はその断片は、IDWGDGGAのCDR2配列を含む。
X1VX2LX3ESGGGLVQX4GGSLRLSCAASGRTIDNYAMAWX5RQAPGKX6X7EX8VX9TIDWGDGGX10RYANSVKGRFTISRDNX11KX12TX13YLQMNX14LX15X16EDTAVYX17CAMARQSRVNLDVARYDYWGQGTX18VTVSS(配列番号4)(式中、X1はE又はQであり、X2はK又はQであり、X3はV又はEであり、X4はA又はPであり、X5はV又はSであり、X6はD又はGであり、X7はL又はRであり、X8はF又はWであり、X9はA又はSであり、X10はA又はTであり、X11はA又はSであり、X12はG又はNであり、X13はM又はLであり、X14はN又はRであり、X15はE又はRであり、X16はP又はAであり、X17はS又はYであり、X18はQ又はLである)、
又はそれと実質的に同一の配列でありうる。代わりに、単離又は精製抗体は、
本明細書においてIGF1R−5と呼ばれる、QVKLEESGGGLVQAGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVATIDWGDGGARYANSVKGRFTISRDNAKGTMYLQMNNLEPEDTAVYSCAMARQSRVNLDVARYDYWGQGTQVTVSS(配列番号5)、
本明細書においてIGF1R−5_H1と呼ばれる、EVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWVRQAPGKGLEWVSTIDWGDGGTRYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号6)、
本明細書においてIGF1R−5_H2と呼ばれる、QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWVRQAPGKGLEWVATIDWGDGGTRYANSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号7)、
本明細書においてIGF1R−5_H3と呼ばれる、QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKGLEFVATIDWGDGGTRYANSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号8)、
本明細書においてIGF1R−5_H5と呼ばれる、QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVATIDWGDGGTRYANSVKGRFTISRDNSKGTMYLQMNSLRAEDTAVYSCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号9)、及び
本明細書においてIGF1R−5_H6と呼ばれる、EVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVSTIDWGDGGTRYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号10)、
又はそれと実質的に同一の配列からなる群から選択される配列を含みうる。
光学イメージング;
ポジトロン放出断層撮影(PET)、検出可能な試剤は、同位体、たとえば11C、13N、15O、18F、64Cu、62Cu、124I、76Br、82Rb及び68Gaであり、18Fが最も臨床的に利用されている;
単光子放出コンピュータ断層撮影(SPECT)、検出可能な試剤は、放射性トレーサー、たとえば、具体的な用途に応じて、99mTc、111In、123I、201Tl、133Xeである。
磁気共鳴画像法(MRI)、検出可能な試剤は、たとえば、これに限定されないが、ガドリニウム、酸化鉄ナノ粒子及び炭素被覆鉄コバルトナノ粒子でありえ、そのことにより、プラークの検出についてMRIの感度を高める。
造影超音波検査(CEUS:Contrast−Enhanced Ultrasonography)又は超音波、検出可能な試剤は、少なくとも1つの音響的に活性で気体が充満したマイクロバブルである。超音波は、ヒト疾患のスクリーニング及び早期検出のために広範に用いられている技術である。それは、MRI又はシンチグラフィーよりも安価であり、放射線を伴わないので、分子的画像診断法、たとえば放射性核種イメージングよりも安全である。
a)対象から脳脊髄液(CSF)を回収するステップ、及び
b)標的化プロテオミクス方法を使用して、CSFにおける1つ又は複数の抗体又はその断片に連結されたカーゴ分子の量を定量するステップ
を含む。
IGF1Rの細胞外ドメインの933アミノ酸長の組換え断片(図1に灰色のボックスで示す、配列番号14のアミノ酸1〜933もまた参照のこと)を調製した。断片は、N末端30アミノ酸シグナルペプチド、全長アルファサブユニット、フューリン切断部位(RKRR、配列番号15、アルファ及びベータサブユニットを分離)を、ベータサブユニットの細胞外部分の大部分とともに含んでいた(図1及び図2)。
5’−CGGGATCCGCCACCATGAAGTCTGGCTCCGGAG−3’(フォワード、配列番号16)
5’−GCTCTAGATCAGAAGTTTTCATATCCTGTTTTGG−3’(リバース、配列番号17)
を使用してPCRにより増幅し、Puc19のSmaI部位内にサブクローニングした。次に、IGF1R933配列を、pCDN4/myc−His(Invitrogen)内にサブクローニングしpIGF1R933−Hisを作製したが、これは、以前に記述されたとおり、His−タグ化外部ドメインの発現を可能にする(Samaniら2004)。
IGF1Rの細胞外ドメインを標的とするVHHを単離するため、ラマを、実施例1で得られた組換えIGF1R933−His断片で免疫化した。
実施例2においてPBMCから単離されたRNAに基づいて、過免疫化ラマVHHライブラリーを構築した。
MJ1:5’−GCCCAGCCGGCCATGGCCSMKGTGCAGCTGGTGGAKTCTGGGGGA−3’(配列番号18)
MJ2:5’−GCCCAGCCGGCCATGGCCCAGGTAAAGCTGGAGGAGTCTGGGGGA−3’(配列番号19)
MJ3:5’−GCCCAGCCGGCCATGGCCCAGGCTCAGGTACAGCTGGTGGAGTCT−3’(配列番号20)、
及び2つのアンチセンスCH2特異的プライマー、
CH2:5’−CGCCATCAAGGTACCAGTTGA−3’(配列番号21)
CH2b3:5’−GGGGTACCTGTCATCCACGGACCAGCTGA−3’(配列番号22)
の等モルミックスによりcDNAを増幅した。
QVKLEESGGGLVQAGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVATIDWGDGGARYANSVKGRFTISRDNAKGTMYLQMNNLEPEDTAVYSCAMARQSRVNLDVARYDYWGQGTQVTVSS(配列番号5)
治療剤のためのBBB担体として適用されたときのラマ由来IGF1R−5の潜在的免疫原性を回避するため、ラクダ科動物由来sdAbを、VHHにおける「ラクダ科動物」残基の変異により「ヒト化」した。ヒト化のため、CDR残基の同定にKabatナンバリング(Kabatら、1991)を使用したことに留意すべきである。
実施例3において同定されたIGF1R−5及び実施例4において構築されたヒト化バージョン(合わせて本明細書において「VHHコンストラクト」と呼ばれる)を、タンパク質発現及び精製のための発現プラスミド内にサブクローニングした。
5’−TATGAAGACACCAGGCCCAGGTAAAGCTGGAGGAGTCT−3’(フォワード、配列番号25)
5’−TTGTTCGGATCCTGAGGAGACGGTGACCTG−3’(リバース、配列番号26)
実施例5において発現させ精製した抗IGF1R VHH IGF1R−5コンストラクトを、サイズ排除クロマトグラフィー、表面プラズモン共鳴解析、及び融解温度解析を使用して特徴づけた。IGF1R−5 VHHのエピトープマッピングもまた実施した。
ff=([θ]T−[θ]U)/([θ]F−[θ]U)……式I
式中、[θ]Tは、任意の温度のモル楕円率であり、[θ]Fは、30℃で完全にフォールドしたタンパク質のモル楕円率であり、[θ]Uは、90℃での未フォールドタンパク質のモル楕円率である。融解温度(Tm)は、グラフソフトウェアGraphPad Prism(Windows用バージョン4.02)を使用して、非線形回帰曲線フィッティング(ボルツマンシグモイド方程式(Boltzman sigmoidal equation))により、アンフォールディング曲線(フォールド率(ff)対温度)の中点として得られた。VHHの融解温度(Tm)を、変性への急激な遷移に相当する観察された変性曲線と一致する二状態系を仮定して楕円率データに基づいて決定した(図2D)。Tm値は、フォールド率(ff)対温度のシグモイド変性曲線の中点でとった。結果を図3Bに示す。すべてのヒト化VHHの融解温度が、IGF1R−5 VHHと比較して改善していた(より高かった)ことから、生物物理学的特性が改善されたことが示唆される。
IGF1R−5が細胞内に内部移行するかどうかを決定するため、svARBEC細胞をCy5−5標識化IGF1R−5とインキュベートした。
マウス抗体結晶性断片(Fc、mFc2b)と融合したIGF1R−5 VHHを含むコンストラクトを調製し、発現させ、単離した。C末端コンストラクト(IGF1R−5−mFc)及びN末端IGF1R−5マウスFc融合コンストラクト(mFc−IGF1R−5)の両方を作製した。それらの配列を図5A〜図5Bに示し、分子の概略図を図5Cに示す。融合タンパク質(約80kDa)はまた、図5A〜図5Bの配列に示されていないN末端シグナルペプチド(MEFGLSWVFLVAILKGVQC、配列番号40)を含んでいた。なぜならそれは、分泌後に切断されるからである。
IGF1R−5−mFc(実施例8)が脳内へと、具体的には脳脊髄液(CSF)中へと透過可能かどうかを決定するとともに、CSF及び血漿におけるその存在を定量するために、インビボアッセイを実施した。
アルブミン比=1nLの解析された血漿当たりの強度/1nLの解析されたCSF当たりの強度
1500以下の比が、血液汚染と考えられた。
実施例8のIGF1R−5 VHH及びコンストラクトが血液脳関門を通過するかどうかを評価するため、下に述べるインビトロアッセイを使用した。実験を要約するフローチャートを図6Aに示す。
IGF1R−5がインビボで血液脳関門(BBB)を通過し、それ自体ではBBBを通過できない分子を、BBBを通過させて「フェリー」できるかどうかを決定するため、神経ペプチドガラニンを、IGF1R−5 VHH又はマウスFcのC若しくはN末端のいずれかに融合されたIGF1R−5に化学的にコンジュゲートし、全身投与した。ガラニンは、脳組織において発現するGalR1及びGalR2に結合することにより鎮痛をもたらす向神経活性ペプチドである。末梢的に与えられた場合、ガラニンは鎮痛効果を有さない。なぜなら、それ自体はBBBを通過できないからである(Robertsonら、2011)。
IGF1R−5−Gal、mFc−IGF1R−5−Gal、及びIGF1R−5−mFc−Gal(実施例11)が血液脳関門を通過するかどうかを評価するため、インビボアッセイを、国際特許公開第2011/127580号に以前に記載のとおり利用した。
末梢投与後にCSFにおいて検出された高レベルのIGF1R−5mFcが、少なくとも部分的に実質細胞外空間に由来すること、言い換えれば、無傷コンストラクトがBBBを横断したことを確認するため、ラット脳におけるIGF1R−5−mFcの免疫検出を実施した。
安全性の観点から、本発明の抗体が、受容体媒介性トランスサイトーシスを介した薬物の送達のために受容体に結合するときに、その受容体の生理機能、すなわち、その天然リガンドであるIGF−1により誘導されるシグナル伝達を妨げないと示すことが重要である。この観点から、IGF1R−5 VHH又はIGF1R−5−mFcが、IGF1R又は関連インスリン受容体(IR)を介してそれらの天然リガンドにより誘導される生理的シグナル伝達を妨げないと実証することが重要である。
本明細書において、また本願全体を通じて参照されたすべての特許、特許出願及び公開が、ここに参照により組み込まれる。
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Claims (16)
- GRTIDNYAの相補性決定領域(CDR)1配列(配列番号1)、
IDWGDGGX(式中、XはA又はTである)のCDR2配列(配列番号2)、及び
AMARQSRVNLDVARYDYのCDR3配列(配列番号3)
を含み、インスリン様成長因子1受容体(IGF1R)に特異的に結合する単離又は精製単一ドメイン抗体又はその抗原結合性断片。 - 配列
X1VX2LX3ESGGGLVQX4GGSLRLSCAASGRTIDNYAMAWX5RQAPGKX6X7EX8VX9TIDWGDGGX10RYANSVKGRFTISRDNX11KX12TX13YLQMNX14LX15X16EDTAVYX17CAMARQSRVNLDVARYDYWGQGTX18VTVSS(配列番号4)(式中、X1はE又はQであり、X2はK又はQであり、X3はV又はEであり、X4はA又はPであり、X5はV又はSであり、X6はD又はGであり、X7はL又はRであり、X8はF又はWであり、X9はA又はSであり、X10はA又はTであり、X11はA又はSであり、X12はG又はNであり、X13はM又はLであり、X14はN又はRであり、X15はE又はRであり、X16はP又はAであり、X17はS又はYであり、X18はQ又はLである)
を含む、請求項1に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片。 - QVKLEESGGGLVQAGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVATIDWGDGGARYANSVKGRFTISRDNAKGTMYLQMNNLEPEDTAVYSCAMARQSRVNLDVARYDYWGQGTQVTVSS(配列番号5);
EVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWVRQAPGKGLEWVSTIDWGDGGTRYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号6);
QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWVRQAPGKGLEWVATIDWGDGGTRYANSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号7);
QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKGLEFVATIDWGDGGTRYANSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号8);
QVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVATIDWGDGGTRYANSVKGRFTISRDNSKGTMYLQMNSLRAEDTAVYSCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号9);及び
EVQLVESGGGLVQPGGSLRLSCAASGRTIDNYAMAWSRQAPGKDREFVSTIDWGDGGTRYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAMARQSRVNLDVARYDYWGQGTLVTVSS(配列番号10)
からなる群から選択される配列を含む、請求項1又は2に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片。 - 前記抗体がラクダ科動物由来である、請求項1〜3のいずれか一項に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片。
- 多価ディスプレイ形式である、請求項1〜4のいずれか一項に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片。
- Fc断片に連結されている、請求項5に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片。
- 表面に固定化されている、請求項1〜6のいずれか一項に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片。
- カーゴ分子に連結されている、請求項1〜6のいずれか一項に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片。
- 前記カーゴ分子が、約1kD〜約200kDaの範囲の分子量を有する、請求項8に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片。
- 前記カーゴ分子が、検出可能な試剤、治療剤、薬物、ペプチド、成長因子、サイトカイン、受容体トラップ、化合物、炭水化物部分、酵素、抗体若しくはその断片、DNAベース分子、ウイルスベクター、若しくは細胞毒性剤;検出可能な試剤、治療剤、薬物、ペプチド、酵素、抗体若しくはその断片、DNAベース分子、ウイルスベクター、若しくは細胞毒性剤が充填された1つ若しくは複数のリポソーム若しくはナノ担体;又は1つ若しくは複数のナノ粒子、ナノワイヤ、ナノチューブ、若しくは量子ドットである、請求項8又は9に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片。
- 1つ又は複数の、請求項1〜10のいずれか一項に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片及び薬学的に許容される担体、希釈剤、又は賦形剤を含む組成物。
- 請求項1〜6のいずれか一項に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片をコードする核酸分子。
- 請求項12に記載の核酸分子を含むベクター。
- a)組織試料を、検出可能な試剤に連結された1つ又は複数の、請求項1〜6のいずれか一項に記載の単離又は精製単一ドメイン抗体又はその抗原結合性断片と接触させるステップ、及び
b)前記組織試料において、IGF1Rに結合した前記単一ドメイン抗体又はその抗原結合性断片に連結された前記検出可能な試剤を検出するステップ
を含む、IGF1Rを検出するインビトロ方法。 - 前記試料が、ヒト又は動物対象からの血清試料、血管組織試料、腫瘍組織試料、又は脳組織試料である、請求項14に記載の方法。
- 前記検出するステップ(ステップb))が、光学イメージング、免疫組織化学、分子画像診断、ELISA、イメージング質量分析、又は他の好適な方法を使用して実施される、請求項14又は15に記載の方法。
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